WO2009113522A1 - Dispersion solide, compositions pharmaceutiques comprenant celle-ci, et procédés de production associés - Google Patents

Dispersion solide, compositions pharmaceutiques comprenant celle-ci, et procédés de production associés Download PDF

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Publication number
WO2009113522A1
WO2009113522A1 PCT/JP2009/054517 JP2009054517W WO2009113522A1 WO 2009113522 A1 WO2009113522 A1 WO 2009113522A1 JP 2009054517 W JP2009054517 W JP 2009054517W WO 2009113522 A1 WO2009113522 A1 WO 2009113522A1
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active ingredient
solid dispersion
carrier
porous
porous carrier
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PCT/JP2009/054517
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English (en)
Japanese (ja)
Inventor
一志 吉田
教道 大窪
純一 坂田
一 金澤
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あすか製薬株式会社
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Priority to ES09718988T priority Critical patent/ES2635767T3/es
Priority to JP2010502820A priority patent/JP5437232B2/ja
Priority to EP09718988.0A priority patent/EP2251038B1/fr
Priority to CA2718255A priority patent/CA2718255C/fr
Priority to CN2009801129958A priority patent/CN102083467B/zh
Priority to US12/922,029 priority patent/US8722094B2/en
Priority to AU2009224418A priority patent/AU2009224418B2/en
Publication of WO2009113522A1 publication Critical patent/WO2009113522A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention includes a solid dispersion using a powdered porous carrier and improved in the dissolution of an active ingredient hardly soluble in water (such as a fibrate active ingredient), and the solid dispersion.
  • the present invention relates to pharmaceutical compositions and methods for producing them.
  • Active ingredients that are sparingly soluble in water have a low elution or dispersibility, so that the bioavailability (bioavailability or bioavailability) is significantly reduced.
  • various pharmaceutical formulations such as refinement of active ingredients, solid dispersions in which active ingredients are dispersed in a carrier that solubilizes active ingredients, powdered porous carriers Solid dispersions in which active ingredients are impregnated and supported are being studied.
  • Patent Document 1 European Patent Publication No. EP330532
  • the bioavailability of fenofibrate can be improved by co-pulverizing a surfactant (particularly sodium lauryl sulfate) and fenofibrate. It is disclosed.
  • Patent Document 2 a biological polymer of fenofibrate is attached to an inert carrier by attaching a fine polymerized fenofibrate and a hydrophilic polymer in which a surfactant is suspended. It is disclosed to improve the availability. However, these preparations still do not have sufficient drug dissolution or dispersibility and their bioavailability is not fully satisfactory. In addition, as the particle size of the active ingredient becomes finer, the handleability decreases.
  • Patent Document 3 JP 2003-500399 A discloses a composition in which a lipid regulator such as fibrate and statin and an excipient such as polyethylene glycol form a eutectic mixture.
  • Patent Document 4 discloses a solid dispersion prepared by melting and mixing fenofibrate with polyethylene glycol and then solidifying, wherein the ratio of fenofibrate to the solid dispersion is 50 mass. % Solid dispersions are disclosed.
  • the carrier component that can be used and melted is greatly restricted depending on the type of the pharmacologically active ingredient.
  • the pharmacologically active component and the carrier component are melt-mixed, they can be applied only to thermally stable components.
  • Non-patent Document 1 Colloidal silica, which is one of porous powders, is used as a carrier, and the solubility of poorly soluble drugs is improved by spray drying from an aqueous system.
  • Non-patent Document 2 carrier colloidal silica is added to indomethacin or tolbutamide to change the crystallinity of the active ingredient and improve the dissolution.
  • Patent Document 5 itraconazole is mixed with an inorganic porous substance (calcium silicate, light anhydrous silicic acid, etc.) to improve the dissolution property of itraconazole.
  • Patent Document 6 itraconazole solution is adsorbed and / or coated on a core substance made of silicic acid or a salt thereof to improve the bioavailability of itraconazole.
  • Japanese Patent Application Laid-Open No. 2006-506388 Patent Document 7 discloses a pharmaceutical composition and a cosmetic composition containing hydrophobic and highly dispersible silicon dioxide having a tamped density of 70 to 400 g / L of silicon dioxide.
  • Patent Document 8 discloses a tablet obtained by tableting a mixture of composite particles obtained by spray-drying a drug such as indomethacin and acetaminophen and silica and other components. .
  • the porous carrier such as silicic acid
  • the solid preparation becomes large even if the solid dispersion is compression-molded.
  • a porous carrier such as silicic anhydride is strongly bound, so that the dispersibility or disintegration property of the solid preparation is lowered, and the elution property of the active ingredient is lowered.
  • Patent Document 9 discloses a drug obtained by treating a composition containing a very poorly water-soluble drug and a porous material with a supercritical liquid or subcritical liquid of carbon dioxide. A containing composition is disclosed. This document also describes an example using true spherical porous silica “Sunsphere H-51” (Asahi Glass Co., Ltd.) together with “Silicia” (Fuji Silysia Co., Ltd.) as silicic acid or a salt thereof. It is described that the dissolution property of the drug from the composition is improved.
  • Patent Document 10 describes a solid oral dosage form comprising a fibrate dissolved in a vehicle (vehicle such as polyethylene glycol) that is hydrophobic, hydrophilic or water miscible, and further enhanced.
  • a solid dosage form comprising a dosage form is disclosed and Aeroperl TM 300 (Degussa) is also described as a carrier or excipient (oil absorbing material).
  • the vehicle is in liquid form, the liquid vehicle is held at a temperature below the melting point of the fibrate, the desired amount of fibrate is dissolved in the vehicle, and the resulting solution is a solid having a temperature below the melting point of the vehicle.
  • a method is also described in which a solid oral dosage form is prepared by spraying on a carrier and mechanically treating the resulting composition to obtain particles, followed by subjecting the particulate material to conventional methods.
  • this method it is necessary to prepare a solid dispersion by heating and dissolving the fibrate in a vehicle, and to spray the molten solid dispersion on a carrier, which requires a special spray device, The operation is complicated. Also, in order to prepare a solid dispersion, a relatively large amount of vehicle is required for the fibrate.
  • an object of the present invention is to provide an active ingredient having a low content in water as compared with conventional preparations in terms of elution or dispersibility of an active ingredient that is sparingly soluble in water (such as a fibrate compound) and bioavailability. Nevertheless, an object of the present invention is to provide a solid dispersion that can be remarkably improved, a method for producing the same, and a pharmaceutical composition (or pharmaceutical preparation) composed of the solid dispersion.
  • Another object of the present invention is to provide a solid dispersion capable of reducing the size of the preparation, a method for producing the same, and a pharmaceutical composition (or pharmaceutical preparation) composed of the solid dispersion.
  • Still another object of the present invention is to provide a solid dispersion that can improve the dissolution of an active ingredient even if it is compression-molded, a method for producing the same, and a pharmaceutical composition (or pharmaceutical preparation) composed of the solid dispersion.
  • Another object of the present invention is to provide a method for easily and easily producing a solid dispersion and a pharmaceutical composition composed of the solid dispersion.
  • the present inventors have determined that a porous silicon-based carrier specific as a porous carrier in a solid dispersion containing a water-insoluble active ingredient (such as a fibrate compound). As a result, it was found that the elution and bioavailability of the active ingredient can be greatly improved by compression molding without treating with a supercritical fluid, and the present invention has been completed.
  • the solid dispersion of the present invention is a solid dispersion composed of an active ingredient that is sparingly soluble in water and a powdery porous carrier impregnated with and supported by the active ingredient.
  • the support When the support is heated at a temperature of 950 ° C. for 2 hours, the support includes a porous silicon-based support with a small weight loss. That is, in the porous silicon-based carrier, the concentration of silanol groups is reduced by heat treatment such as surface treatment or baking with an organic or inorganic coupling agent. For example, after drying and removing moisture, the porous silicon-based carrier is reduced when it is heated at a temperature of 950 ° C.
  • the powdery porous carrier may be composed of at least a porous silicon-based carrier having the above characteristics.
  • the solid dispersion is prepared without being treated with a supercritical fluid or a subcritical fluid.
  • the solid dispersion of the present invention can be obtained without spraying the porous dispersion with the melt of the solid dispersion in which the active ingredient is dissolved or dispersed in the form of molecular or fine particles in the matrix component.
  • the active ingredient may be impregnated and supported on a porous carrier, and is usually supported uniformly.
  • the porous silicon-based carrier having heat loss characteristics may be composed of a spherical porous silicon-based carrier, and the porous silicon-based carrier may be calcined silica (fumed silica).
  • the absorption intensity at wave number 3800 cm -1 I 0, the absorption intensity I 1 at the wave number 3650 cm -1, the absorption intensity at wave number 3600 cm -1 I 2, the absorption intensity I 3 at wave number 3550 cm -1, the absorption intensity I 4 at wave number 3500 cm -1, the absorption intensity I 5 at wavenumber 3450 cm -1, the absorption intensity at wave number 3400 cm -1 I 6 the absorption intensity I 7 at wavenumber 3350 cm -1, I 8 the absorption intensity at wave number 3300 cm -1, the absorption intensity I 9 at wavenumber 3200 cm -1, the absorption intensity at wave number 3100 cm -1 was I 10
  • the porous silicon-based carrier exhibits
  • the porous silicon-based carrier may have an average particle diameter of 1 to 50 ⁇ m by a laser diffraction method, a specific surface area of 250 to 1200 m 2 / g by a BET method, and a pore volume of 0.5 to 5 ml / g.
  • the porous silicon carrier may be spherical silica having a weight loss of 3.0% by weight or less after heating at a temperature of 950 ° C. for 2 hours, an oil absorption of 200 to 400 ml / 100 g, and a specific surface area of 300 to 1000 m 2 / g.
  • the porous silicon-based support may be monodisperse particles having an infinite number of fine pores in the nanometer unit and occupying 50 to 85% of the particle volume.
  • the porous silicon-based carrier may have a sedimentation volume (apparent specific gravity) of 10 to 50 ml / 5 g by a stationary method.
  • the porous silicon-based carrier may be spherical silica (such as spherical silicon dioxide).
  • the porous carrier may be composed of the porous silicon-based carrier having the heating loss characteristic alone, or may be composed of the porous silicon-based carrier having the heating weight loss characteristic and another porous carrier.
  • the active ingredient may be a physiologically active ingredient or a pharmacologically active ingredient.
  • the pharmacologically active ingredient include hyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics, antithrombotic agents, antidiabetic agents, antidiabetic complications and the like.
  • the pharmacologically active ingredient is a fibrate compound such as bezafibrate, clinofibrate, clofibrate, fenofibrate, beclobrate, vinylibrate, ciprofibrate, etofibrate, gemfibrozil, nicofibrate, pilifibrate, lonfibrate, simfibrate, simfibrate , Theophibrate or a free acid thereof, or an active metabolite or a salt thereof.
  • the supported amount of the active ingredient may be about 0.01 to 5 parts by weight with respect to 1 part by weight of the powdery porous carrier. *
  • the crystalline active ingredient may be supported on a porous carrier in a crystalline, semi-crystalline or amorphous form. In many cases, the crystalline active ingredient is supported in an amorphous form.
  • the porous carrier may further carry a water-soluble additive component in addition to the active ingredient.
  • the porous carrier may further carry at least one additive component among water-soluble polymer, saccharide, surfactant and lipid.
  • Additive components are vinyl pyrrolidone homo- or copolymer, polyvinyl alcohol, acrylic acid homo- or copolymer, polyethylene glycol, cellulose ethers, sugars, sugar alcohols, anionic surfactants and nonionic surfactants It may be at least one selected from agents.
  • the ratio of each additive component may be 1 to 30 parts by weight with respect to 100 parts by weight of the active ingredient hardly soluble in water, and the total amount of the additive component is hardly soluble in water.
  • Active ingredients and additive components water-soluble additive components
  • Active ingredients and additive components water-soluble additive components that are sparingly soluble in water are usually impregnated and supported uniformly throughout the porous carrier.
  • the active ingredient that is sparingly soluble in water is treated with a supercritical fluid (such as a supercritical carbon dioxide fluid) or a subcritical fluid (such as a subcritical carbon dioxide fluid) without being treated with water.
  • a solid dispersion supported on the substrate is produced.
  • an organic solvent solution of the sparingly soluble active ingredient room temperature, particularly a liquid solution at a temperature of 10 ° C.
  • a powdery porous carrier containing the porous silicon-based carrier having the heat loss characteristics By removing the organic solvent, a solid dispersion in which the active ingredient is supported on the porous carrier can be produced.
  • the organic solvent solution may contain at least one component selected from water-soluble polymers, saccharides, and surfactants.
  • the organic solvent solution is usually a liquid at a temperature of 10 ° C., and the powdered porous carrier is immersed in the organic solvent solution at room temperature, the powdered porous carrier is impregnated with the organic solvent solution, the mixture is dried, and the organic solvent is dried. May be removed. More specifically, a solid dispersion can be produced by spray drying a mixed solution of an organic solvent solution of an active ingredient and a powdered porous carrier.
  • the present invention also includes a pharmaceutical composition composed of the solid dispersion.
  • This pharmaceutical composition may comprise a plurality of active ingredients, and at least one active ingredient may be an active ingredient that is sparingly soluble in water.
  • at least an active ingredient hardly soluble in water may be supported on a powdery porous carrier containing the porous silicon carrier having the heat loss characteristics.
  • it may be a pharmaceutical composition comprising an active ingredient having a large dosage and an active ingredient having a small dosage, at least the active ingredient having a large dosage being an active ingredient hardly soluble in water.
  • at least an active ingredient hardly soluble in water may be supported on the powdery porous carrier.
  • the pharmaceutical composition may be a pharmaceutical composition comprising a fibrate compound and a statin compound, wherein at least the fibrate compound is supported on a powdery porous carrier containing the porous silicon carrier having the heat loss characteristics.
  • the pharmaceutical composition may further comprise at least one carrier component selected from excipients, binders, disintegrants and lubricants.
  • the pharmaceutical composition is preferably a preparation (solid preparation) in which a solid dispersion is compression-molded.
  • a pharmaceutical composition is produced through at least a step of compressing the solid dispersion.
  • solid dispersion means a dispersion in which an active ingredient is dispersed and supported on a solid porous carrier as a porous matrix in a fine particle or molecular state, and is a meltable organic material.
  • a meltable dispersion (solid dispersion) in which an active ingredient is dissolved or dispersed in a fine or molecular state in a solid matrix (non-porous matrix) does not include a form supported on a solid porous carrier.
  • the porous silicon-based carrier having the heat loss characteristic may be simply referred to as “first porous carrier”, and the other porous carrier may be simply referred to as “second porous carrier”. .
  • the first porous carrier (specific porous silicon-based carrier) is used as the porous carrier of the solid dispersion, the elution or dispersibility of the active ingredient hardly soluble in water can be greatly improved. Therefore, the bioavailability can be greatly improved regardless of the content of the active ingredient which is smaller than that of the conventional preparation. Further, since the first porous carrier is used, the preparation (pharmaceutical composition or pharmaceutical preparation) can be reduced in size, and patient compliance can be improved. Furthermore, the elution property of the active ingredient can be greatly improved even by compression molding. Also, it was composed of solid dispersion and solid dispersion by simple operation of impregnation and drying without treatment with supercritical fluid (supercritical carbon dioxide fluid etc.) or subcritical fluid (subcritical carbon dioxide fluid etc.) A pharmaceutical composition can be easily produced.
  • supercritical fluid supercritical carbon dioxide fluid etc.
  • subcritical fluid subcritical carbon dioxide fluid etc.
  • FIG. 1 is an infrared absorption spectrum of the first porous carrier used in Examples 1 to 7.
  • FIG. 2 is an infrared absorption spectrum of the second porous carrier used in Examples 4 to 7.
  • FIG. 3 is a graph showing the results of dissolution tests of the tablets of Examples 1 to 7 and the control preparation.
  • FIG. 4 is a graph showing the results of the absorption test of the tablet of Example 3 and the control preparation.
  • FIG. 5 is an infrared absorption spectrum of the first porous carrier used in Example 8.
  • FIG. 6 is a graph showing the results of the dissolution test of the tablet of Example 8 and the control preparation.
  • FIG. 7 is a graph showing the results of the dissolution test of the tablets of Example 11 and Comparative Example 1.
  • FIG. 8 is an infrared absorption spectrum of the first porous carrier used in Example 25.
  • FIG. 9 is a graph showing the results of the dissolution test of the tablet of Example 25 and the control preparation.
  • the solid dispersion of the present invention comprises an active ingredient that is sparingly soluble in water and a powdery porous carrier that is impregnated with and supported by the active ingredient.
  • the active ingredient is usually supported by impregnating or penetrating a powdered porous carrier as a porous matrix, and is uniformly supported throughout the powdered porous carrier.
  • the solid dispersion of the present invention comprises a supercritical fluid (such as a supercritical carbon dioxide fluid) or a subcritical fluid (subcritical fluid) containing a composition containing an active ingredient hardly soluble in water and a powdered porous carrier.
  • meltable dispersion solid dispersion
  • active ingredient By heating a meltable dispersion (solid dispersion) in which the active ingredient is dissolved or dispersed in a fine or molecular state in a meltable organic solid matrix.
  • the molten solid dispersion is prepared without being sprayed and supported on a solid porous carrier.
  • the solubility of the sparingly soluble active ingredient in water is 1 mg / mL or less, preferably 0.1 mg / mL or less, more preferably 0.01 mg / mL or less at a temperature of 25 ° C.
  • the hardly soluble active ingredient may have physiological activity or may have pharmacological activity.
  • the kind of the poorly soluble active ingredient is not particularly limited, for example, hyperlipidemia treatment agent, angina treatment agent, hypertension treatment agent, hypotension treatment agent, anti-obesity agent, heart failure treatment agent, myocardial infarction treatment agent, Antiarrhythmic agent, antidiabetic agent, antidiabetic complication agent, peptic ulcer agent, antipyretic agent, analgesic agent, anti-inflammatory agent, healthy stomach / digestion / antacid / antiemetic agent, antitussive expectorant, bronchial asthma agent , Constipation treatment, diarrhea treatment, liver disease treatment, biliary / spleen treatment, acupuncture treatment, thyroid disease treatment, hyperuricemia treatment, rheumatism treatment, antibiotic, antidepressant, antiallergy Drugs, antituberculosis drugs, prostatic hypertrophy treatment drugs, osteoporosis treatment drugs, Alzheimer's disease treatment drugs
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors such as simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, cerivastatin, itavastatin, ZD-4522 or salts thereof (eg, sodium salt, calcium salt, etc. )
  • Statin compounds fibrate compounds, probucol, nicotinic acid drugs (eg, nicomol, niceritrol, etc.), ethyl icosapentate, plant sterols (eg, soysterol), small intestine cholesterol transporter inhibitors (eg, Examples thereof include ezetimibe) and anion exchange resins (colestimide, cholestyramine).
  • Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors (eg, temocapril, cilazapril, trandopril or salts thereof), angiotensin II antagonists (eg, candesartan cilexetil, eprosartan, valsantan, telmisartan, irbesartan, olmesartan medoxomil) , Tasosartan or salts thereof), calcium antagonists (eg, manidipine, nifedipine, nicardipine, amlodipine, efonidipine or salts thereof), potassium channel openers (eg, levucomacarim), clonidine hydrochloride, bunazosin hydrochloride, etc. It is done.
  • angiotensin converting enzyme inhibitors eg, temocapril, cilazapril, trandopril or salts thereof
  • Anti-obesity agents include, for example, central anti-obesity agents (for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase Inhibitors (for example, orlistat), ⁇ 3 agonists, peptidic appetite suppressants (for example, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (for example, linchtripto), and the like.
  • central anti-obesity agents for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.
  • pancreatic lipase Inhibitors for example
  • therapeutic agents for heart failure include xanthine derivatives (for example, sodium salicylate theobromine, calcium salicylate theobromine), thiazide compounds (for example, ethiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflutide , Polythiazide, methiclotiazide, etc.), non-thiazide compounds (methiclan, trypamide, etc.), anti-aldosterone compounds (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide compounds (For example, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid,
  • heparin eg, heparin sodium, heparin calcium, dalteparin sodium
  • warfarin antithrombin drug (eg, argatroban)
  • thrombolytic drug eg, Urokinase, tisokinase,reteplase, nateplase, monteplase, pamitepase, etc.
  • platelet aggregation inhibitors for example, dibilidamole, cilostazol, icosapentate, etc.
  • Antidiabetic agents include, for example, insulin preparations, ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, etc.), biguanides (eg, phenformin or salts thereof), insulin secretagogues [sulfonylurea agents (eg, Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol, etc.), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate]], dipeptidyl peptidase IV inhibitor, ⁇ 3 Agonists, amylin agonists (eg, pramlintide), phosphotyrosine phosphatase inhibitors (eg, vanadic acid, etc.), gluconeogenesis inhibitors (eg, glycogen phospho) Lylase inhibitor
  • therapeutic agents for diabetic complications include aldose reductase inhibitors (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, etc.), neurotrophic factors (for example, NGF, NT-3, etc.) , Neurotrophic factor production / secretion promoter, PKC inhibitor, AGE inhibitor, active oxygen scavenger (eg, thioctic acid), and cerebral vasodilator.
  • aldose reductase inhibitors for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, etc.
  • neurotrophic factors for example, NGF, NT-3, etc.
  • Neurotrophic factor production / secretion promoter for example, PKC inhibitor, AGE inhibitor, active oxygen scavenger (eg, thioctic acid), and cerebral vasodilator.
  • therapeutic agents for peptic ulcer include proton pump inhibitors (for example, omeprazole, lansoprazole, etc.), defense factor enhancers (for example, teprenone, metoclopramide, sofalcone, etc.) and the like.
  • proton pump inhibitors for example, omeprazole, lansoprazole, etc.
  • defense factor enhancers for example, teprenone, metoclopramide, sofalcone, etc.
  • therapeutic agent for rheumatism examples include immunosuppressants (for example, leflunomide, methotrexate, etc.), salazosulfapyridine, auranofin and the like.
  • antiallergic agents examples include antihistamines (for example, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, pranlukast hydrate, bepotastine besylate, etc.).
  • antihistamines for example, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, pranlukast hydrate, bepotastine besylate, etc.
  • vitamin A vitamin A
  • vitamin B vitamin B 12 (mecobalamin)
  • vitamin C vitamin D
  • vitamin E etc.
  • minerals amino acids and the like
  • These active ingredients may be optically active or racemic. These active ingredients can be used alone or in combination of two or more.
  • the fibrate compounds include, for example, bezafibrate, clinofibrate, clofibrate, fenofibrate, beclobrate, vinyl fibrate, ciprofibrate, etofibrate, gemfibrozil, nicofibrate, pilifibrate, lonfibrate, simfibrate Synfibrate, theofibrate, or a salt thereof (for example, clofibrate aluminum, etc.).
  • Fibrates include derivatives of active compounds (esters, hydrates, hydrates, etc.), prodrugs, free acids or active metabolites (fibric acid, clofibric acid, fenofibric acid, etc.) or their salts. It is.
  • the fibrate compound may be fenofibrate and the free acid or active metabolite (fenofibric acid) corresponding to fenofibrate.
  • the fibrate compound may be an optically active substance or a racemate.
  • the fibrate compounds can be used alone or in combination of two or more.
  • the fibrate compound may contain other active ingredients (for example, other antihyperlipidemic drugs excluding the fibrate compound (such as HMG-CoA reductase inhibitor (statin compound)), antihypertensive agent, anti-obesity agent , At least one selected from diuretics, antithrombotics, antidiabetics, diabetic complications, and the like.
  • Fibrate compounds reduce low density lipoprotein binding (LDL) cholesterol and triglycerides (TG) and increase high density lipoprotein binding (HDL) cholesterol by inhibiting triglyceride synthesis or secretion in the liver. It is useful as a prophylactic and / or therapeutic agent for hyperlipidemia.
  • LDL low density lipoprotein binding
  • TG triglycerides
  • HDL high density lipoprotein binding
  • fenofibrate having a large lipid improving action, particularly LDL cholesterol or triglyceride lowering action is preferable.
  • the active ingredient may be amorphous or crystalline. Even if it is a crystalline active ingredient, the solid dispersion of the present invention can greatly improve the dissolution property. Therefore, even if the amount of active ingredient used is small, the bioavailability can be greatly improved.
  • the dosage form can be miniaturized and the bioavailability can be increased even if the dose is reduced. it can. Therefore, the present invention is preferably applied to an active ingredient that is sparingly soluble in water and has low bioavailability, and an active ingredient with a small dose (for example, a single dose of 0.1 to 15 mg, preferably May be applied to about 0.5 to 10 mg, more preferably about 1 to 5 mg).
  • a small dose for example, a single dose of 0.1 to 15 mg, preferably May be applied to about 0.5 to 10 mg, more preferably about 1 to 5 mg.
  • active ingredients that are sparingly soluble in water have low bioavailability, and have a large dosage (for example, a single dose is 25 to 1000 mg, preferably 30 to 500 mg, more preferably about 50 to 300 mg) It is preferable to apply to.
  • high-dose active ingredients include antihyperlipidemic agents (eg, fibrate compounds (eg, fenofibrate), probucol, nicotinic acid agents), anti-obesity agents, heart failure agents, myocardium Examples include infarction treatment drugs, diabetes treatment drugs, diabetic complication treatment drugs, and the like.
  • a plurality of active ingredients may be supported on a porous carrier.
  • an active ingredient having a large dosage for example, a fibrate compound such as fenofibrate
  • an active ingredient having a small dosage for example, pitavastatin
  • Or a statin compound such as pitavastatin calcium may be supported on a porous carrier.
  • the hardly soluble active ingredient is supported on the porous carrier, and the hardly soluble active ingredient and the water-soluble active ingredient may be supported on the porous carrier.
  • a powdery porous carrier containing a porous silicon carrier (first porous carrier) having a weight loss of 4% by weight or less when heated at a temperature of 950 ° C. for 2 hours is used. That is, the powdery porous carrier is composed of at least the first porous carrier (porous silicon carrier) having the heat loss characteristics.
  • the first porous carrier includes an inorganic silicon compound such as silicon oxide (silicon dioxide, hydrous silicon dioxide, silica, etc.), a silicate compound [eg, silicic acid (eg, light anhydrous silicic acid), silicate ( For example, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminum silicate, magnesium silicate aluminate, magnesium magnesium metasilicate, etc.)] can be used.
  • a silicate compound eg, silicic acid (eg, light anhydrous silicic acid), silicate ( For example, calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminum silicate, magnesium silicate aluminate, magnesium magnesium metasilicate, etc.)] can be used.
  • the first porous carrier can be used alone or in combination of two or more. These first porous carriers are often composed of silicon dioxide (including hydrous silicon dioxide) or silica.
  • the silicon-based carrier may be untreated or may have silanol groups (for example, about 2 to 5.5% by weight, preferably about 2.5 to 5% by weight of silanol groups based on the whole). Good.
  • silanol groups for example, about 2 to 5.5% by weight, preferably about 2.5 to 5% by weight of silanol groups based on the whole.
  • the carrier has a high binding ability (shaping ability) and is suitable for use as an excipient.
  • the silicon-based carrier has, for example, a silanol group concentration of 0.5 to 4% by weight, preferably 1 to 3.5% by weight, more preferably 1.5 to 3% by weight (for example, The carrier may be reduced or adjusted to about 1.5 to 2.5% by weight.
  • the silicon-based carrier is treated with a surface treatment agent or a surface modifier (such as a coupling agent) and / or heat treatment such as firing to produce a silanol group. May be reduced or adjusted.
  • organic coupling agents organic acids such as organic carboxylic acids or their anhydrides, acid halides, (poly) isocyanate compounds such as aliphatic (poly) isocyanate, aromatic (poly) isocyanate, etc. , Aliphatic (poly) amines, (poly) amines such as aromatic (poly) amines, epoxy compounds, etc.) or inorganic coupling agents.
  • Examples of the inorganic coupling agent include alkoxysilanes [mono C 1-4 alkyltri C 1 such as tetra C 1-4 alkoxysilane such as tetramethoxysilane and tetraethoxysilane, methyltrimethoxysilane and ethyltriethoxysilane.
  • alkoxysilanes dimethyldimethoxysilane, di-C 1-4 alkyl di C 1-4 alkoxysilane such as diethyl diethoxy silane, trimethyl monomethoxy silane, tri C 1-4 alkyl mono- C 1-4, such as triethyl monoethoxy silane alkoxysilane, etc.]; arylalkoxy silanes [phenyltrimethoxysilane, monoaryl tri C 1-4 alkoxy silane such as phenyl triethoxysilane, diphenyldimethoxysilane, and diphenyl diethoxy silane Jiari Alkoxysilanes having a mercapto group such as 3-mercaptopropyltrimethoxysilane, 3-mercaptopropyl triethoxysilane; alkoxysilane having a haloalkyl group such as 3-chloropropyltriethoxysilane; di C 1-4 alkoxys, di
  • the usage-amount of these surface treating agents can be selected in the range which does not impair the shaping property. Moreover, the usage-amount of a surface treating agent can be evaluated using an infrared absorption spectrum as a parameter
  • the heat treatment such as firing is performed in an atmosphere containing oxygen-containing gas (air, etc.), inert gas (eg, rare gas such as nitrogen gas, helium gas, argon gas, carbon dioxide gas, etc.), hydrogen gas, etc., at a temperature of 500-2000.
  • the reaction can be performed at a temperature of about 0 ° C. (preferably 800 to 1700 ° C., more preferably 1000 to 1500 ° C.).
  • the heat treatment time may be, for example, about 10 minutes to 24 hours (eg, 30 minutes to 12 hours, particularly 1 to 6 hours).
  • the first porous carrier may be calcined silica (fumed silica). Further, the first porous carrier may be granulated. For granulation, a conventional granulation method such as rolling granulation or fluidized bed granulation can be used, and granulation may be performed in accordance with the surface treatment and / or heat treatment.
  • the loss on heating is 4% by weight or less (preferably 3.5% by weight or less, more preferably 3.0% by weight or less, particularly 2.5% by weight or less, for example, 2% by weight or less).
  • the loss on heating may be about 0.3 to 3.5% by weight (for example, 0.5 to 3% by weight), or 0 to 2.5% by weight (for example, 0 to 2% by weight). %) Degree.
  • Such heat loss is dried (drying at 105 ° C.
  • the Japanese Pharmacopoeia 2.43 “Ignition Loss Test Method”, etc. it can be measured by heating at a temperature of 950 ° C. for 2 hours and calculating the weight loss of the carrier after heating.
  • the first porous carrier may be in the form of particles, and the shape of the first porous carrier may be amorphous, spherical, elliptical, polyhedral, prismatic, etc. It is often a shape (especially spherical).
  • the preparation can be reduced in size due to high fluidity and small bulk density, and the preparation workability of the preparation including processes such as handling and tableting can be improved.
  • the first porous carrier (silicon-based carrier) usually shows an absorption peak at a wave number of 3400 to 3500 cm ⁇ 1 (for example, a wave number of 3440 to 3480 cm ⁇ 1 ) in an infrared absorption spectrum. Depending on the measurement conditions, the absorption intensity may vary in the wave number range.
  • the first porous carrier has an absorption in the infrared absorption spectrum of at least a wave number of 3100 to 3550 cm ⁇ 1 , particularly 3200 to 3400 cm ⁇ 1 (for example, 3300 to 3350 cm ⁇ 1 ), compared with light anhydrous silicic acid. It has the feature of low strength.
  • the absorption intensity at wave number 3800 cm -1 I 0, the absorption intensity I 1 at the wave number 3650 cm -1, the absorption intensity I 2 at wavenumber 3600 cm -1, wave number 3550cm the absorption intensity at -1 I 3, the absorption intensity at a wavenumber 3500cm -1 I 4, I 5 the absorption intensity at wave number 3450 cm -1, I 6 the absorption intensity at wave number 3400 cm -1, wave number 3350 cm -1 the absorption intensity I 7 in, I 8 the absorption intensity at wave number 3300 cm -1, when the absorption intensity I 9 at wavenumber 3200 cm -1, the absorption intensity at wave number 3100 cm -1 was I 10, at least one
  • the intensity ratio may be as follows.
  • Intensity ratio to absorption intensity I 0 (1-1) Intensity ratio (I 1 / I 0 ): 1 to 7 (for example, 2 to 6.7), preferably 3 to 6.5 (for example, 3. 5 to 6.5), more preferably 3.7 to 6.3 (eg 4 to 6.2), especially 4.5 to 6.3 (eg 5 to 6.2) (1-2) Intensity ratio (I 2 / I 0 ): 1 to 19 (eg, 2 to 18.5, especially 5 to 18.5), preferably 8 to 18 (eg, 8.5 to 17.5), more preferably The intensity ratio (I 2 / I 0 ) may be as follows: 9 to 17 (eg, 9.2 to 16.7), particularly about 10 to 18 (eg, 11 to 17).
  • the intensity ratio (I 4 / I 0 ) may be as follows: Intensity ratio (I 4 / I 0 ): 3 to 15 (eg 4 to 12), preferably 4.5 to 10 (eg 5 to 10), more preferably 5.5 to 9 (eg 6 to 8) About 5), especially about 6.5 to 8 (1-5)
  • the intensity ratio (I 6 / I 0 ) may be as follows: 35 to 85 (eg, 40 to 80), especially about 45 to 75.
  • the intensity ratio (I 8 / I 0 ) may be as follows: 13 to 30 (eg, 14 to 27), especially about 15 to 25.
  • Intensity ratio (I 9 / I 0 ): 1 to 12 (eg 3 to 11), preferably 4.5 to 10.5 (eg 5 to 10), Preferably 5.5 to 9.5 (eg, 5.6 to 9), usually 6.0 to 12 (eg, 6.2 to 11), particularly about 6.2 to 10 intensity ratio (I 9 / I 0 ) may be as follows: Intensity ratio (I 9 / I 0 ): 1 to 5 (eg, 1.5 to 4.5), preferably about 2 to 4 (eg, 2.5 to 3.5) (1-10) Intensity ratio ( I 10 / I 0 ): 0.5 to 4.5 (eg 1 to 4.5), preferably 1.2 to 4.3 (eg 1.3 to 4.2), more preferably 1.
  • the intensity ratio (I 10 / I 0 ) may be as follows. Intensity ratio (I 10 / I 0 ): 0.5 to 3 (eg 1 to 3), preferably 1.2 to 2.5 (eg 1.5 to 2.5), in particular 1.2 to 2 About 0.
  • Intensity ratio to absorption intensity I 1 (2-1) Intensity ratio (I 3 / I 1 ): 3.5 to 5.8 (for example, 3.7 to 5.7), preferably 3.8 to 5.8 (eg, 3.9 to 5.7), more preferably 4 to 5.8 (eg, 4.2 to 5.7), particularly 4.5 to 5.8 (eg, 4.6 to About 5.7) (2-2) Intensity ratio (I 4 / I 1 ): 6 to 10.5, preferably 6.3 to 10.3 (for example, 6.5 to 10.3), more preferably 6.7 to 10.2 (eg, 6.8 to 10), particularly about 7.7 to 10.5 (eg, 7.8 to 10) (2-3) Intensity ratio (I 5 / I 1 ): 7 to 15, preferably 7.5 to 14.7 (eg 8 to 14.5), more preferably 8.5 to 14.3 (eg 9 to 14), usually 9.5 to 15 (eg 9.8-14.8), especially About 10 to 14.5 (2-4) Intensity ratio (I 6 / I 1
  • Intensity ratio to absorption intensity I 2 (3-1) Intensity ratio (I 4 / I 2 ): 3 to 3.9 (eg, 3.2 to 3.9), preferably 3.2 to 3. 8 (for example, 3.1 to 3.7), particularly about 3.3 to 3.9 (for example, 3.4 to 3.8) (3-2) Intensity ratio (I 5 / I 2 ): 3. 5 to 5.6, preferably 3.7 to 5.5, more preferably 3.8 to 5.4 (eg 4 to 5.4), usually 4.2 to 5.6 (eg 4.
  • the intensity ratio to the absorption intensity I 0 (preferably, at least one of the intensity ratios (1-1) to (1-10), particularly the intensity ratio (1-1) to (1-9) at least one intensity ratio, in particular at least one of the intensity ratios (1-2) to (1-8)) and (2) the intensity ratio to the absorption intensity I 1 (particularly the intensity At least one of the ratios (2-1) to (2-6), particularly at least one of the intensity ratios (2-2) to (2-5) is a silanol group or a hydroxyl group. It is useful for distinguishing from a porous silicon-based carrier having a high concentration (for example, an amorphous porous carrier such as light anhydrous silicic acid).
  • an intensity ratio with respect to the absorption intensity I 2 (especially at least one of the intensity ratios (3-1) to (3-5), particularly the intensity ratios (3-1) to (3-3) (At least one strength ratio) can also be a useful indicator for identifying the first porous support.
  • the first porous carrier only needs to show at least one of the above-described strength ratios, and may be a plurality of strength ratios (for example, two strength ratios (I 2 / I 0 ) and strength ratio (I 3 / I 0 )). One intensity ratio) or all intensity ratios.
  • the intensity ratio based on the infrared absorption spectrum can be calculated based on the absorption intensity at each wave number by mixing and measuring about 200 mg of KBr and about 2 mg of carrier in a mortar according to the KBr method, preparing a plate.
  • the absorption intensity at a predetermined wave number can be represented by the height from the baseline in the infrared absorption spectrum chart.
  • a small absorption intensity value (for example, absorption intensity I 0 , I 1, etc.) can be measured accurately by expanding the infrared absorption spectrum, and in a region where the absorption intensity varies.
  • the value of the absorption intensity (for example, absorption intensity I 5 , I 6, etc.) averages the intensity of the fluctuation range of the infrared absorption spectrum, draws a gentle curve or straight line as a whole, and shows the intersection with a predetermined wave number as the intensity. Can be used as
  • the average pore diameter of the first porous carrier is, for example, an average pore diameter of 5 to 40 nm, preferably 7 to 35 nm, more preferably about 10 to 30 nm (for example, 15 to 25 nm).
  • the average pore diameter of the first porous carrier is preferably somewhat large, for example, 10 to 40 nm, preferably 12 to 35 nm, more preferably 13 to 30 nm ( For example, it is advantageously about 15 to 25 nm.
  • the oil absorption amount of the first porous carrier is, for example, 75 to 500 (preferably 100 to 450, more preferably 150 to 400, particularly 200 to 380). (For example, about 220 to 350), usually about 230 to 320.
  • the oil absorption amount of the first porous carrier is preferably high. For example, it is about 175 to 500 (preferably 190 to 450, more preferably about 200 to 400, particularly about 220 to 380 (for example, 230 to 350), and usually about 230 to 320.
  • the average particle size of the first porous carrier by the laser diffraction method is, for example, 1 to 50 ⁇ m, preferably 2 to 45 ⁇ m (for example, 3 to 40 ⁇ m), more preferably 3 to 35 ⁇ m (for example, 5 to 30 ⁇ m). It may be a degree.
  • the average particle size of the first porous carrier is, for example, 1 to 25 ⁇ m (eg 7 to 25 ⁇ m), preferably 2 to 20 ⁇ m (eg 8 to 15 ⁇ m), more preferably 3 to 15 ⁇ m (eg 9 About 13 ⁇ m) or about 8 to 22 ⁇ m (for example, 10 to 12 ⁇ m).
  • the specific surface area (unit: m 2 / g) of the first porous carrier by the BET method is, for example, 250 to 1200 (preferably 300 to 1000, more preferably 350 to 900, particularly 400 to 800 (for example, 400 to 400).
  • the pore volume (unit: ml / g) of the first porous carrier is, for example, 0.5 to 5 (preferably 0.7 to 3, more preferably 0.8 to 2.5, especially about 1 to 2.
  • the sedimentation volume (apparent specific gravity, unit: ml / 5 g) of the first porous carrier by the stationary method is, for example, 10 to 50 (preferably 15 to 45). More preferably, it is about 20 to 40).
  • the first porous carrier has innumerable fine pores in the nanometer unit (the average pore diameter) inside, and is 50 to 85% (for example, 55 to 83%, preferably 60 to 80%) of the particle volume. More preferably, the space may occupy 65 to 80% (for example, about 70 to 80%).
  • the particle size distribution of the first porous carrier may be polydispersed, but is preferably monodispersed.
  • the first porous carrier is composed of monodisperse particles (for example, in a volume-based particle size distribution, the particle size distribution width D90 when the particle size having a cumulative frequency of 10% is D10 and the particle size having a cumulative frequency of 90% is D90.
  • / D10 may be about 1.2 to 3, preferably 1.3 to 2.7, and more preferably 1.5 to 2.5 (eg, 1.85 to 2.3).
  • the pH of the 5 wt% water slurry of the first porous carrier may be about 4 to 8 (for example, 5 to 7).
  • the average pore diameter of such a carrier is about 12 to 35 nm, preferably about 13 to 30 nm (for example, 15 to 25 nm), and may be about 15 to 20 nm.
  • the BET specific surface area (unit: m 2 / g) is, for example, about 400 to 900 (eg, 450 to 850), preferably about 500 to 800 (eg, 500 to 750).
  • the oil absorption (unit: ml / 100 g) is about 200 to 500 (eg, 220 to 450), preferably about 230 to 400 (eg, 230 to 350), and may be about 230 to 320.
  • the bulk density is small and the active ingredient is supported stably and in a fine particle or molecular state. Performance can be greatly improved and the size of the preparation can be reduced. Also, the dissolution of the active ingredient can be improved by preparing granules and tablets by compression molding.
  • a first porous carrier eg, spherical porous silica
  • the first porous carriers are “Cyrossphere” product numbers “C-1504” and “C-1510” (manufactured by Fuji Silysia Chemical Co., Ltd.), “Aero Pearl AEROPERL” product numbers “300/30” (Degussa) Available from Degussa).
  • the first porous carrier can be obtained in a spherical form (a form such as spherical porous silica).
  • the form of the active ingredient is not particularly limited, and may be crystallized or in an amorphous state.
  • the active ingredient even if the active ingredient is crystalline, it can be supported on a first porous carrier (spherical porous silica or the like) having the heat loss characteristics in an amorphous form. That is, even if the crystalline active ingredient is supported on the first porous carrier (spherical porous silica or the like) having the above heat loss characteristics and subjected to X-ray diffraction and thermal analysis, the peak or endothermic peak caused by the crystal Is not observed. Therefore, in this invention, even if it is a crystalline active ingredient, an elution property can be improved effectively.
  • the powdery porous carrier may be composed of the first porous carrier alone, If necessary, the first porous carrier and the second porous carrier may be used.
  • the second porous carrier include cellulose such as crystalline cellulose (such as porous cellulose), resin (ion exchange resin, thermoplastic resin, thermosetting resin, etc.), inorganic substance [activated carbon, minerals (zeolite, diatomaceous earth).
  • metal oxides alumina, zinc oxide, titanium dioxide, etc.
  • metal hydroxides alkaline earth metal hydroxides such as calcium hydroxide; aluminum hydroxide, etc.
  • metal carbonates Such as alkaline earth metal carbonates such as calcium carbonate
  • metal sulfates such as alkaline earth metal sulfates such as calcium sulfate
  • metal phosphates such as alkaline earth metal phosphates such as calcium phosphate
  • the second porous carrier is preferably a porous silicon carrier, and examples of the porous silicon carrier include silicon dioxide (including hydrous silicon dioxide) or silica, silicate compounds [light silicic anhydride, silica Calcium silicate, magnesium silicate, aluminum silicate, magnesium aluminum silicate, magnesium magnesium silicate, synthetic magnesium sodium silicate, colloidal hydrous aluminum silicate, etc.], diatomaceous earth, zeolite, and the like. These second porous carriers can also be used alone or in combination of two or more.
  • the second porous carrier may be amorphous or spherical (including a shape such as an ellipse).
  • amorphous or spherical carrier As the amorphous or spherical carrier, light anhydrous silicic acid, calcium silicate, magnesium silicate, magnesium aluminum silicate, and magnesium aluminate silicate are often used.
  • amorphous light anhydrous silicic acid is often used as the amorphous second porous carrier.
  • the amorphous light anhydrous silicic acid include, for example, the Silicia series manufactured by Fuji Silysia Chemical Co., Ltd. Available as Adsolider series (AdSolider 101, AdSolider 102, etc.), Aerosil series (Aerosil 200, Aerosil 300, etc.) manufactured by Nippon Aerosil Co., Ltd.
  • a spherical second porous carrier may be used.
  • Such a spherical second porous carrier is available, for example, as “Sunsphere” product numbers “H-51”, “H-52”, “H-53” (manufactured by Asahi Glass Co., Ltd.).
  • “Sunsphere” product numbers “H-51”, “H-52”, “H-53” manufactured by Asahi Glass Co., Ltd.
  • the spherical second porous carrier it is possible to improve the manufacturing workability of the preparation including processes such as handleability and tableting due to high fluidity and small bulk density.
  • the second porous carrier may contain more hydroxyl groups (or silanol groups) than the first porous carrier.
  • the loss on heating (loss on ignition) of the second porous carrier is, for example, 4.5% by weight or more (for example, 5 to 17% by weight), particularly 5 to 15% by weight ( For example, it may be about 7 to 10% by weight.
  • the porous silicon carrier as the second porous carrier may have the following intensity ratio in the infrared absorption spectrum.
  • Intensity ratio to absorption intensity I 0 (1-11) Intensity ratio (I 1 / I 0 ): 2.5 to 15 (for example, 5 to 12, particularly 6 to 12), preferably 7 to 10 (for example, 7.3 to 9.5), more preferably about 7.5 to 9 (for example, 7.5 to 8.5) (1-12) Intensity ratio (I 2 / I 0 ): 5 to 30 (for example, 7 to 28, especially 10 to 27), preferably 15 to 25 (for example, 19 to 23), more preferably about 19.5 to 22.5.
  • the intensity ratio (I 2 / I 0 ) was as follows: May be.
  • the intensity ratio (I 8 / I 0 ) may be as follows: Good.
  • the intensity ratio (I 9 / I 0 ) may be as follows.
  • the intensity ratio (I 10 / I 0 ) may be as follows. Intensity ratio (I 10 / I 0 ): preferably 2.5 to 6.5 (eg 3 to 6), more preferably 3.5 to 5.5 (eg 3.5 to 5), especially 3. About 7 to 4.7.
  • Intensity ratio to absorption intensity I 1 (2-11) Intensity ratio (I 3 / I 1 ): 4 to 10 (eg, 4.5 to 10), preferably 5 to 8 (eg, 5.5 to 7.5), more preferably about 5.7 to 7 (for example, 5.8 to 6.5). (2-12) Intensity ratio (I 4 / I 1 ): 7 to 15, preferably 8 to 13 ( For example, 10 to 13), more preferably about 10.5 to 12.5 (for example, 10.5 to 12).
  • these porous silicon-based carriers may also exhibit at least one of the above-described strength ratios, such as a plurality of strength ratios (for example, strength ratio (I 2 / I 0 ) and strength ratio (I 3 / I 0 )). Two intensity ratios) or all intensity ratios.
  • the average particle diameter of the second porous carrier is not particularly limited, and can be appropriately selected from, for example, a range of about 1 to 20 ⁇ m, 2 to 15 ⁇ m, preferably 3 to 10 ⁇ m, particularly 4 to 10 ⁇ m (for example, 4 to 8 ⁇ m). ) Degree.
  • the second porous carrier also has a large number of fine pores, and the average pore diameter is, for example, 1 to 30 nm, preferably 2 to 27 nm (for example, 3 to 25 nm), more preferably 5 to 22 nm (for example, 6 to 20 nm).
  • the average pore volume of the second porous carrier is, for example, 0.1 to 5 mL / g, preferably 0.3 to 3 mL / g, more preferably 0.5 to 2 mL / g (for example, 0. 7 to 1.75 mL / g), particularly about 1 to 1.7 mL / g.
  • the specific surface area of the second porous carrier is not particularly limited, and is, for example, 100 to 1000 m 2 / g (for example, 200 to 800 m 2 / g), preferably 250 to 750 m 2 / g (for example, 300 to 700 m 2). / G) degree.
  • the oil absorption amount (unit: ml / 100 g) of the second porous carrier is, for example, about 75 to 500 (preferably 90 to 400, more preferably 100 to 350, particularly 150 to 350 (eg 170 to 320)). It is.
  • the sedimentation volume (apparent specific gravity, unit: ml / 5g) of the second porous carrier by the stationary method is, for example, about 10 to 120 (preferably 20 to 110, more preferably 30 to 100).
  • the silicon-based porous carrier as the second porous carrier may have a silanol group in the same manner as the first porous carrier, and the first porous carrier is used to reduce or adjust the concentration of the silanol group.
  • the surface treatment may be performed with the surface treatment agent in the same manner as the quality carrier.
  • the ratio of the first porous carrier (eg, spherical porous carrier) and the second porous carrier (eg, amorphous porous carrier) can be selected within a range that does not impair the dissolution of the active ingredient.
  • the latter (weight ratio) 50/50 to 100/0 (eg 55/45 to 99/1), preferably 60/40 to 100/0 (eg 65/35 to 95/5), more preferably 70 / 30 to 100/0 (for example, 75/25 to 90/10), particularly about 75/25 to 100/0.
  • the amount of the active ingredient supported on the powdery porous carrier is 0.01 to 10 parts by weight (for example, 0.01 to 10 parts by weight) of the active ingredient relative to 1 part by weight of the powdery porous carrier depending on the type of carrier and active ingredient.
  • the elution property of an active ingredient is high, and bioavailability can be improved greatly. Therefore, high bioavailability can be achieved while reducing the amount of active ingredient used.
  • the amount of active ingredient used is reduced by about 10 to 50% by weight, preferably 20 to 45% by weight (for example, 25 to 35% by weight) with respect to the amount of active ingredient used in the past. Even so, the same bioavailability as before can be obtained.
  • the powdery porous carrier functions as an excipient, the solid dispersion has high compression moldability. Therefore, the dosage form can be miniaturized, and the dosage and patient compliance can be improved.
  • the solid dispersion is not limited to the active ingredient, and may contain various pharmaceutically acceptable formulation components (or carrier components, additive components) such as excipients, binders, disintegrants, and the like.
  • carrier components or additive components
  • the impregnation and dissolution properties of the active component from water-soluble polymers, excipients, and surfactants It is preferable to use at least one selected, and lipids may be used to control the dissolution of the active ingredient.
  • the solid dispersion is at least selected from water-soluble polymers, saccharides, surfactants, lipids, etc.
  • One kind of component may be further contained, and these components may be supported on the carrier together with the active ingredient or may be supported on a carrier different from the carrier of the solid dispersion.
  • the additive component is a water-soluble component (in particular, at least one water-soluble component selected from water-soluble polymers, sugars, and surfactants).
  • additive components have low affinity or compatibility with water-insoluble active ingredients (or hydrophobic active ingredients), and the active ingredients are in a molecular form.
  • a component that cannot be dissolved or dispersed in the form of fine particles additive component that cannot form a meltable solid dispersion in which the active ingredient is dissolved or dispersed at the molecular level or fine particle level and does not function as a solid matrix of the solid dispersion
  • additive component that cannot form a meltable solid dispersion in which the active ingredient is dissolved or dispersed at the molecular level or fine particle level and does not function as a solid matrix of the solid dispersion
  • water-soluble polymers examples include soluble starch; polysaccharides such as gum arabic, dextrin, sodium alginate, hyaluronic acid, sodium chondroitin sulfate; polyvinylpyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (copovidone), etc.
  • Vinylpyrrolidone homo- or copolymer polyvinyl alcohol; carboxyvinyl polymer (Carbopol 934, 940, Carbomer etc.), polyacrylic acid polymer, polymethacrylic acid polymer (Eudragit L, LD, S etc.) ) Acrylic acid homopolymers or copolymers; Synthetic polymers such as polyethylene glycol (eg macrogol); methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose Loin potassium, hydroxyethyl cellulose (HEC), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), cellulose ethers such as hydroxypropylmethylcellulose (HPMC) is exemplified.
  • Synthetic polymers such as polyethylene glycol (eg macrogol); methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose Loin potassium, hydroxyethyl cellulose (HEC), hydroxyethyl cellulose, hydroxypropyl cellulose (H
  • a water-soluble polymer can be used individually or in combination of 2 or more types.
  • vinylpyrrolidone homopolymers or copolymers such as polyvinylpyrrolidone (povidone), homopolymers or copolymers of acrylic acid such as carboxyvinyl polymers and polyacrylic acid polymers, polyethylene glycol (Macrogol) Etc.), and cellulose ethers such as HPMC and HPC are preferred.
  • polyvinylpyrrolidone (povidone) carboxyvinyl polymer, polyethylene glycol (such as macrogol), HPMC, and HPC are preferable.
  • HPMC includes HPMC 2208, HPMC 2906, HPMC 910, etc.
  • HPC includes about 53 to 78% HPC of hydroxypropoxy groups.
  • water-soluble polymer at least one water-soluble cellulose ether selected from HPMC and HPC is often used.
  • saccharide examples include lactose, sucrose, glucose, fructose, sucrose, maltose (malt sugar), reduced maltose, maltitol, mannitol, sorbitol, xylitol and other sugars (monosaccharides or oligosaccharides such as disaccharides) or sugars.
  • sugars examples include alcohols.
  • sugar alcohols such as mannitol are preferred.
  • surfactant examples include anionic surfactants (for example, sulfonic acids such as benzenesulfonic acid, dodecylbenzenesulfonic acid, and dodecanesulfonic acid or salts thereof; alkyl sulfates such as sodium dodecyl sulfate and sodium lauryl sulfate (SLS).
  • anionic surfactants for example, sulfonic acids such as benzenesulfonic acid, dodecylbenzenesulfonic acid, and dodecanesulfonic acid or salts thereof
  • alkyl sulfates such as sodium dodecyl sulfate and sodium lauryl sulfate (SLS).
  • sulfoaliphatic dicarboxylic acid ester salts for example, sulfosuccinates such as disodium lauryl sulfosuccinate); long chain fatty acid metal salts such as calcium stearate; bile acids or the like Salt; cholic acid such as cholic acid and deoxycholic acid), cationic surfactant (tetraalkylammonium salt such as tetraalkylammonium halide; benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride, etc.), nonionic Surfactants (sucrose long chain fatty acid esters such as sucrose palmitate, sucrose stearate, sucrose oleate; ethylene glycol mono or distearate, polyethylene glycol mono or dioleate, polyethylene glycol mono Or (poly) ethylene glycol long chain fatty acid
  • anionic surfactants for example, C 10-24 sodium alkylsulfate such as SLS, sulfosuccinate, etc.
  • nonionic surfactants for example, sucrose C 8-26 fatty acid ester (Poly) glycerin C 8-26 fatty acid ester, sorbitan C 8-26 fatty acid ester, (poly) oxyethylene sorbitan long chain fatty acid ester such as polysorbate, etc.
  • polyoxyethylene polyoxypropylene glycol such as pluronic and poloxamer, etc. preferable.
  • polyoxyethylene polyoxypropylene glycol as a polymer type surfactant can be classified as a nonionic surfactant.
  • Lipids include waxes (beeswax, carnauba wax, cacao butter, lanolin, paraffin, petrolatum, etc.), long chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols (poly C 2-4 alkylene glycol) , Esters with glycerin or polyglycerin) (oils and fats such as hardened oil such as glyceride and hardened castor oil), phospholipids, higher alcohols (saturated or unsaturated higher alcohols such as stearyl alcohol and oleyl alcohol), Examples include higher fatty acids (saturated or unsaturated higher fatty acids such as oleic acid, linoleic acid, linolenic acid and stearic acid), metal soaps (for example, fatty acid metal salts such as sodium coconut oil fatty acid and calcium stearate) and the like. Lipids alone or in combinations of two or more Can be used together.
  • the amount of these components to be supported or used can be selected according to the characteristics of the solid dispersion, and is usually 0.1 to 100 parts by weight (for example, 1 to 50 parts by weight) with respect to 100 parts by weight of the active ingredient. Part), preferably 0.5 to 50 parts by weight, more preferably 1.5 to 30 parts by weight (for example, 2.5 to 25 parts by weight), usually 1.5 to 20 parts by weight. It may be about (for example, 1.5 to 15 parts by weight).
  • the amount of each additive component used can be selected from the range of 3 to 50 parts by weight, preferably 5 to 30 parts by weight (eg, 7 to 25 parts by weight) with respect to 100 parts by weight of the active ingredient. It may be about 5 to 20 parts by weight (for example, 5 to 15 parts by weight).
  • the additive component and the active component are heated and melt-mixed, and the solid component (the additive component as a vehicle or a solid matrix contains the active component in a molecular or fine particle form). It is not necessary to prepare a meltable dispersion (solid dispersion).
  • the powdery porous carrier composed of the first porous carrier functions as an excipient for the solid preparation, and the additive component includes the wettability and impregnation of the active ingredient to the powdery porous carrier. Improve sexiness. Furthermore, the dissolution property and bioavailability of the active ingredient can be improved. Therefore, the amount of the additive component used can be greatly reduced, and the dosage form can be miniaturized.
  • the ratio of each additive component (for example, a component selected from a water-soluble polymer, a saccharide, and a surfactant) carried on the porous carrier is, for example, 100 parts by weight of an active component that is hardly soluble in water.
  • 0.1 to 30 parts by weight for example, 0.5 to 25 parts by weight
  • preferably 1 to 20 parts by weight for example, 1.5 to 20 parts by weight
  • more preferably 2 to 15 parts by weight for example, 2.5 to 13 parts by weight
  • the amount of each additive component used is 1 to 30 parts by weight (for example, 2 to 25 parts by weight), preferably 3 to 20 parts by weight (for example, 5 to 20 parts by weight) with respect to 100 parts by weight of the active ingredient.
  • the total amount of the additive components is, for example, 1 to 100 parts by weight with respect to 100 parts by weight of the water-insoluble active ingredient (fenofibrate component and the like).
  • it can be selected from a range of about 1 to 50 parts by weight (eg 3 to 50 parts by weight), preferably 5 to 40 parts by weight (eg 5 to 30 parts by weight), more preferably 10 to 40 parts by weight ( For example, it may be about 10 to 30 parts by weight), particularly about 10 to 25 parts by weight.
  • a solid dispersion in which the active ingredient is supported on a powdery porous carrier can be produced without treatment with a supercritical fluid (such as supercritical water) or a subcritical fluid (such as subcritical water). That is, the organic solvent solution of the sparingly soluble active ingredient is impregnated into a powdery porous carrier composed of at least the first porous carrier, and the organic solvent is removed, whereby the active ingredient becomes the porous carrier.
  • a solid dispersion supported on the substrate can be produced.
  • a matrix component and an active component are heated and melted to prepare a meltable dispersion (solid dispersion) in which the active component is dissolved or finely dispersed in the matrix component, and the solid dispersion is melted to obtain a carrier.
  • a meltable dispersion solid dispersion
  • the active ingredient is not thermally deteriorated and can be applied to a wide range of active ingredients, and the elution property and bioavailability of the active ingredient can be improved simply and efficiently.
  • the organic solvent only needs to be able to dissolve the hardly soluble active ingredient (and the water-soluble polymer), for example, alcohols (methanol, ethanol, propanol, isopropanol, butanol, etc.), esters (ethyl acetate, acetic acid, etc.).
  • alcohols methanol, ethanol, propanol, isopropanol, butanol, etc.
  • esters ethyl acetate, acetic acid, etc.
  • An organic solvent can be used individually or in mixture of 2 or more types. If necessary, water may be used in combination as long as the solution
  • the concentration of the organic solvent solution is 1 to 50 wt / vol%, preferably 5 to 30 wt / vol% (for example, 10 to 25 wt / vol%), more preferably 7 to 20 wt / vol% (for example, in terms of solid content) 10-15 wt / vol%).
  • the organic solvent solution containing the sparingly soluble active ingredient is usually a liquid (liquid form) at room temperature (temperature 15 to 25 ° C.), preferably 10 ° C., more preferably 5 ° C., particularly 0 ° C. It is.
  • the porous carrier is impregnated in the form of an organic solvent solution
  • the active ingredient and the additive component are not carried unevenly on the surface of the porous carrier, and penetrate into the deep part of the porous carrier uniformly. , And can be supported uniformly throughout.
  • an organic solvent solution containing the additive component for example, at least one component selected from a water-soluble polymer, a saccharide, and a surfactant
  • the permeability or impregnation property of the sparingly soluble active component to the porous carrier is improved. It can be improved.
  • the organic solvent solution containing the hardly soluble active ingredient may be brought into contact with the powdered porous carrier, and the organic solvent solution may be applied to the porous carrier by spraying, etc.
  • the porous carrier is left in the organic solvent solution under stirring or standing, or the organic solvent solution and the porous carrier are mixed and impregnated.
  • the powdered porous carrier is immersed in an organic solvent solution at room temperature, and the powdered porous carrier is impregnated with the organic solvent solution.
  • the active ingredient in the organic solvent enters the pores of the porous carrier and is supported. It should be noted that most of the active ingredient seems to enter or be adsorbed into the pores of the porous carrier.
  • the impregnation operation is usually performed under normal pressure in many cases, but may be performed under reduced pressure or under pressure as necessary.
  • the impregnation operation can be carried out at a temperature lower than the boiling point of the organic solvent, and the temperature is usually 0 to 50 ° C., preferably 5 to 35 ° C. (for example, 10 to 30 ° C.), more preferably 15 to 25 ° C. Can be done to the extent.
  • the impregnation operation can be performed at room temperature (for example, about 10 to 35 ° C., preferably about 15 to 30 ° C., particularly about 15 to 25 ° C.). If necessary, it may be impregnated by heating or heating. Furthermore, if necessary, the porous carrier impregnated with the active ingredient may be separated and washed by a method such as filtration or centrifugation.
  • the mixture (a mixture containing a powdery porous carrier impregnated with an active ingredient) is dried to remove the organic solvent to obtain a solid dispersion. That is, by removing the remaining organic solvent from the powdery porous carrier, a dispersion (solid dispersion) in which the active ingredient is dispersed in the porous carrier can be obtained.
  • the active ingredient is usually uniformly dispersed and supported on a porous carrier.
  • the porous carrier is impregnated with the organic solvent solution without spraying and supporting the melt of the solid dispersion containing the meltable matrix and the active ingredient on the porous carrier, the active ingredient and the additive are added.
  • the components are usually supported throughout the porous carrier.
  • the removal of the organic solvent can be performed by a conventional method, for example, drying (air drying, heat drying), or can be performed under normal pressure or reduced pressure.
  • a solid dispersion can be efficiently produced by removing a solvent by freeze-drying or spray-drying a mixed solution of an organic solvent solution of an active ingredient and a powdered porous carrier.
  • a mixed liquid of the organic solvent solution and the powdered porous carrier is spray-dried, a homogeneous solid dispersion can be efficiently produced.
  • This freeze-drying or spray-drying can be performed by a conventional method.
  • spray-drying can be performed by spraying the mixture into an air stream and drying it with warm air / hot air.
  • the solid dispersion of the present invention is only required that the active ingredient is impregnated and supported on the porous carrier, and may be a mixture of the active ingredient and the porous carrier, and the active ingredient is usually uniform in the porous carrier. Are dispersed and supported. In particular, since the active ingredient is dispersed in a state where the active ingredient is taken into the pores of the porous carrier, the dissolution of the active ingredient can be remarkably improved, and even if the amount of active ingredient used is reduced, Can improve the scientific availability.
  • the solid dispersion of the present invention may be used alone as a medicine, and is excellent in compression moldability. Therefore, it may be used as a granule by compression molding, crushing and sizing, and tableting It may be used as a tablet.
  • the solid dispersion of the present invention is often used as a pharmaceutical composition such as a solid preparation in combination with a pharmaceutically acceptable carrier or additive (such as the exemplified carrier or additive).
  • the pharmaceutical composition of the present invention only needs to contain the solid dispersion in which an active ingredient hardly soluble in water is supported on a powdery porous carrier composed of the first porous carrier, Multiple active ingredients may be included. It suffices that at least one of the plurality of active ingredients is an active ingredient that is sparingly soluble in water, and the plurality of active ingredients may be composed of a plurality of active ingredients that are sparingly soluble in water. It may contain a water-soluble active ingredient. In addition, all the plurality of active ingredients may be supported on a single porous carrier (first porous carrier), and each of the plurality of active ingredients is a plurality of porous carriers (at least the first porous carrier).
  • a plurality of powdered porous carriers are not necessarily the specific powdery porous carriers used in the present invention.
  • all or some of the active ingredients may be supported on the powdery porous carrier.
  • Other active ingredients not supported on the porous carrier can be contained in the pharmaceutical composition in various forms.
  • an active ingredient with a low dose (such as a poorly water-soluble active ingredient) may be supported on a porous carrier, but at least administered It is preferable that a large amount of the active ingredient is supported on a porous carrier (a powdery porous carrier composed of at least the first porous carrier, particularly the first porous carrier).
  • a porous carrier a powdery porous carrier composed of at least the first porous carrier, particularly the first porous carrier.
  • an active ingredient having a large dose and hardly soluble in water is supported on a porous carrier (a powdery porous carrier composed of at least the first porous carrier, particularly the first porous carrier).
  • a fibrate compound in a pharmaceutical composition containing a fibrate compound (eg, fenofibrate) and a statin compound (pitavastatin or pitavastatin calcium, etc.) Is preferably contained in the form of a solid dispersion supported on a powdered porous carrier, and the statin compound may be supported on a porous carrier, and is free from the solid dispersion (such as a mixture or a preparation). In the form) may be included in the pharmaceutical composition.
  • a preparation containing a small amount of active ingredient can be added in various steps of the pharmaceutical composition. For example, when a granule containing a solid dispersion is prepared and then tableted to produce a tablet, preparation of the granule It may be added in the process, or may be added to the granules and tableted.
  • Low-dose active ingredients include angina, antihypertensive, hypotensive, antiobesity, heart failure, myocardial infarction, antiarrhythmic, diabetes, and diabetic complications
  • Drugs peptic ulcer drugs, antipyretic drugs, analgesics, anti-inflammatory drugs, healthy stomach / digestion / antacids / antiemetics, antitussives, bronchial asthma drugs, constipation drugs, diarrhea drugs, liver disease drugs , Biliary / spleen system, acupuncture, thyroid disease, hyperuricemia, rheumatism, antibiotic, antidepressant, antiallergic, antituberculosis, prostatic hypertrophy, osteoporosis Therapeutic agents, Alzheimer's disease therapeutic agents, and the like.
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors such as simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, cerivastatin, itavastatin, pravastatin, fluvastatin or salts thereof (eg, sodium salt, calcium salt) And the like, and small intestine cholesterol transporter inhibitors (for example, ezetimibe).
  • HMG-CoA reductase inhibitors such as simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, cerivastatin, itavastatin, pravastatin, fluvastatin or salts thereof (eg, sodium salt, calcium salt) And the like, and small intestine cholesterol transporter inhibitors (for example, ezetimibe).
  • Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors (for example, captopril, enalapril, delapril, imidapril, quinapril, temocapril, cilazapril, trandopril, lisinipril, or salts thereof), angiotensin II antagonists (for example, candesartan cilexetil) , Losartan, valsantan, telmisartan, olmesartan medoxomil or salts thereof), calcium antagonists (eg, manidipine, nifedipine, nicardipine, amlodipine, efonidipine or salts thereof), clonidine hydrochloride, bunazosin hydrochloride and the like.
  • angiotensin converting enzyme inhibitors for example, captopril, enalapril, delapril, imidapril, quinapri
  • anti-obesity drugs examples include central anti-obesity drugs (for example, mazindol).
  • therapeutic agents for heart failure include thiazide compounds (eg, trichloromethiazide, hydrochlorothiazide, etc.), non-thiazide compounds (eg, tripamide), anti-aldosterone compounds (eg, spironolactone), chlorobenzenesulfonamide compounds (eg, , Mefluside, indapamide, etc.), azosemide, isosorbide nitrate, piretanide, bumetanide and the like.
  • thiazide compounds eg, trichloromethiazide, hydrochlorothiazide, etc.
  • non-thiazide compounds eg, tripamide
  • anti-aldosterone compounds eg, spironolactone
  • chlorobenzenesulfonamide compounds eg, Mefluside, indapamide, etc.
  • azosemide isosorbide nitrate, piretanide
  • Examples of the therapeutic agent for myocardial infarction include warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), platelet aggregation inhibitor (eg, ethyl icosapentate, beraprost sodium), aspirin And clopidogrel sulfate.
  • warfarin eg, warfarin potassium
  • antithrombin drug eg, aragatroban
  • platelet aggregation inhibitor eg, ethyl icosapentate, beraprost sodium
  • aspirin And clopidogrel sulfate examples include warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), platelet aggregation inhibitor (eg, ethyl icosapentate, beraprost sodium), aspirin And clopidogrel sulfate.
  • Examples of the therapeutic agent for diabetes include insulin preparations, ⁇ -glucosidase inhibitors (eg, voglibose, miglitol, etc.), insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, glimepiride, etc.), insulin resistance improvers (pioglitazone hydrochloride) Etc.).
  • ⁇ -glucosidase inhibitors eg, voglibose, miglitol, etc.
  • insulin secretagogues eg, tolbutamide, glibenclamide, gliclazide, glimepiride, etc.
  • insulin resistance improvers pioglitazone hydrochloride
  • therapeutic agents for diabetic complications include active oxygen scavengers (for example, thioctic acid) and cerebral vasodilators (for example, thioprid).
  • active oxygen scavengers for example, thioctic acid
  • cerebral vasodilators for example, thioprid
  • peptic ulcer therapeutic agents examples include proton pump inhibitors (eg, omeprazole, lansoprazole, etc.), defense factor enhancers (eg, metoclopramide, etc.) and the like.
  • Examples of the therapeutic agent for rheumatism include immunosuppressants (for example, leflunomide, methotrexate, etc.), auranofin and the like.
  • antiallergic agents examples include antihistamines (eg, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, bepotastine besylate, etc.).
  • antihistamines eg, clemastine fumarate, loratadine, mequitazine, ebastine, oxatomide, bepotastine besylate, etc.
  • the form of the pharmaceutical composition may be, for example, a single preparation or a kit preparation.
  • a pharmaceutical composition comprising a combination of a fibrate compound (eg, fenofibrate) and a statin compound (eg, pitavastatin)
  • at least the fibrate compound is a powdered porous carrier
  • it may be a single pharmaceutical composition (formulation) comprising (a) a solid dispersion in which a fibrate compound is supported on the powdery porous carrier and a statin compound.
  • both a fibrate compound and a statin compound may be a single pharmaceutical composition (formulation) comprising a solid dispersion supported on the powdery porous carrier, and (c) a fibrate compound.
  • a kit-form pharmaceutical composition comprising a preparation containing a solid dispersion supported on the powdered porous carrier and a preparation containing a statin compound. It may be a formulation).
  • the dosage form is not particularly limited, and is a semi-solid preparation (cream, jelly, gummi, ointment, gel, etc.), liquid (suspension, emulsion, syrup, etc.), etc.
  • semi-solid preparation cream, jelly, gummi, ointment, gel, etc.
  • liquid uspension, emulsion, syrup, etc.
  • solid preparations powder, granules (granules, fine granules, etc.), pills, pills, tablets (including sublingual tablets, orally disintegrating tablets, lozenges, chewable tablets, etc.)
  • capsules hard capsules, soft capsules, microcapsules, etc.
  • dry syrups suppositories, film-form preparations, sheet-form preparations, etc.
  • the capsule may be a liquid-filled capsule (soft capsule or the like), or a capsule filled with a solid agent such as a solid dispersion or a granule.
  • the powder and / or liquid may be an injection, a spray, or an aerosol.
  • the preparation may be an oral administration preparation or a parenteral administration preparation (eye drops, nasal drops, inhalants, patches (such as cataplasms)). Further, the preparation may be a topical preparation (such as a suppository).
  • the pharmaceutical composition of the present invention may be an immediate release preparation or a sustained release preparation, if necessary.
  • the preparations of the present invention are often solid preparations for oral administration, such as powders, tablets (bare tablets, etc.), granules, pills, capsules and films, and tablets, granules and capsules are preferred.
  • the carrier may be, for example, the Japanese Pharmacopoeia (Pharmacopeia), (1) Pharmaceutical Additive Handbook, Maruzen ), (1989), (2) “Pharmaceutical Additives Dictionary 2000” (Pharmaceutical Daily Journal, published in March 2002), (3) “Pharmaceutical Additives Dictionary 2005” (Pharmaceutical Daily Report, published in May 2005), (4) Ingredients (for example, excipients) listed in Pharmacology, Rev. 5th edition, Nanedo Co., Ltd. (1997), and (5) Pharmaceutical Additives Standard 2003 (Pharmaceutical Daily Newsletter, August 2003) Agent, binder, disintegrant, lubricant, coating agent, etc.).
  • the carrier of the pharmaceutical composition particularly, solid preparation
  • at least one carrier selected from excipients, binders and disintegrants is often used, and additives such as lipids may be used.
  • the solid dispersion of the present invention does not impair the elution of the active ingredient even when compression molded. More specifically, for example, when a solid dispersion is prepared using light anhydrous silicic acid (for example, “Silicia 350”) and compression-molded, the elution property of the active ingredient from the molded body (sized granule or tablet). Is greatly impaired. On the other hand, even if the solid dispersion of the present invention is compression molded, it can greatly improve the dissolution of the active ingredient.
  • the present invention is usually applied to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one carrier component selected from components subjected to a compression molding process, for example, an excipient, a binder, a disintegrant and a lubricant.
  • a carrier component selected from components subjected to a compression molding process, for example, an excipient, a binder, a disintegrant and a lubricant.
  • the present invention is advantageous when applied to a solid preparation in which a solid dispersion is compression molded.
  • excipient examples include saccharides or sugar alcohols such as lactose, sucrose, glucose, sucrose, mannitol, sorbitol, and xylitol; starches such as corn starch and potato starch; crystalline cellulose (including microcrystalline cellulose) and the like.
  • sugars examples include sugars; silicon oxides or silicates such as light anhydrous silicic acid and synthetic aluminum silicate; and phosphates such as anhydrous calcium hydrogen phosphate.
  • soluble starch such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as agar, gum arabic, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, pectin, sodium chondroitin sulfate; polyvinylpyrrolidone, polyvinyl alcohol , Synthetic polymers such as carboxyvinyl polymer, polyacrylic acid polymer, polylactic acid, polyethylene glycol; cellulose ethers such as methylcellulose, ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. It can be illustrated.
  • Disintegrators include calcium carbonate, carboxymethylcellulose or salts thereof (such as carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium), polyvinylpyrrolidone (polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone (crospovidone), etc.), low degree of substitution Examples thereof include hydroxypropylcellulose and sodium starch glycolate.
  • lipid examples include the waxes exemplified above, long chain fatty acid esters, higher alcohols, phospholipids, higher fatty acids, metal soaps, and the like.
  • Carriers can be used alone or in combination of two or more.
  • the proportion of the carrier is not particularly limited, and is, for example, 1 to 500 parts by weight, preferably 5 to 300 parts by weight, more preferably 10 to 250 parts by weight (for example, 25 to 200 parts by weight) with respect to 100 parts by weight of the active ingredient. Part) degree.
  • lubricants examples include talc, magnesium stearate, calcium stearate, polyethylene glycol 6000, and the like.
  • Additives include disintegration aids, antioxidants or antioxidants, surfactants, emulsifiers, dispersants, suspension agents, solubilizers, thickeners (carboxyvinyl polymer, polyvinyl alcohol, gelatin, etc.
  • Water-soluble polymers cellulose ethers such as carboxymethyl cellulose), pH adjusters or buffers (citric acid-sodium citrate buffer, etc.), preservatives or preservatives (parabens such as methyl paraben and butyl paraben), Bactericides or antibacterial agents (benzoic acids such as sodium benzoate), antistatic agents, corrigents or masking agents (for example, sweeteners), colorants (such as dyes and pigments such as Bengala), flavoring agents or fragrances (fragrances) Agents), cooling agents, antifoaming agents and the like.
  • An additive can be used individually or in combination of 2 or more types.
  • the solid preparation may be coated with a coating agent.
  • the coating agent include saccharides, cellulose derivatives such as ethyl cellulose and hydroxyethyl cellulose, polyoxyethylene glycol, enteric components (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, Eudragit). (Methacrylic acid-acrylic acid copolymer) and the like, and gastric soluble components (polymers containing basic components such as dialkylaminoalkyl (meth) acrylate (such as Eudragit)).
  • the formulation (unit: mg) of a pharmaceutical composition (such as a solid preparation such as a tablet) in a typical unit dosage form containing at least a fibrate compound (particularly fenofibrate or its free acid or active metabolite) as an active ingredient is as follows: As shown in the table.
  • carrier functions also as an excipient
  • the pharmaceutical composition of the present invention is prepared by a conventional method such as a solid dispersion containing an active ingredient, a carrier component (pharmaceutically acceptable formulation component), and additives as necessary, for example, the 15th revised Japanese pharmacy. It can be prepared by the production method described in this method or a method according to this production method.
  • a solid agent can be prepared using a carrier component (such as at least one carrier selected from a binder, an excipient, and a disintegrant) together with a solid dispersion containing an active ingredient.
  • a granule can be prepared by granulating an active ingredient-containing solid dispersion and a carrier component (pharmaceutically acceptable formulation component) by extrusion granulation, spray granulation or the like, and adjusting the size as necessary.
  • Tablets can be produced by mixing the granulated product with carrier components and / or additives as necessary and compression molding. Moreover, you may coat a compression molding agent as needed.
  • Capsules can be prepared by filling capsules with granules.
  • the solid dispersion of the present invention is excellent in compression moldability. Therefore, it is suitable for producing a pharmaceutical composition through at least a step of compressing the solid dispersion.
  • the solid dispersion can be compression-molded with carrier components (excipients, etc.), the molded body can be crushed and sized to obtain granules, and the mixture of solid dispersion and carrier components can be compressed. Tablets can be produced by molding (tabletting), and tablets can be produced by compression molding (tabletting) the mixture of the granule and carrier component.
  • the pharmaceutical composition of the present invention can be applied to non-human animals, but is usually used for humans.
  • the content of the active ingredient in the preparation, the dosage of the preparation and the administration schedule include the type of active ingredient, the subject of administration, the age, weight, sex and condition (general condition, medical condition, etc.), administration time, dosage form It can be appropriately selected depending on the administration method and the like.
  • the content of the active ingredient in the preparation is, for example, 0.01 to 90% by weight, preferably 0.05 to 80% by weight, more preferably 0.1 to 70% by weight in terms of solid content with respect to the whole preparation. % (For example, 0.5 to 50% by weight).
  • the content of the fibrate compound in the preparation is, for example, 1 to 90% by weight, preferably 5 to 80% by weight, more preferably 10 to 70% by weight (eg 15 to 50% by weight). %) Degree.
  • the dose of the fibrate compound is 1 to 500 mg, preferably 5 to 300 mg (eg 10 to 250 mg), more preferably 30 to 200 mg (eg 50 to 50 mg) per day for an adult (body weight of about 60 kg). About 150 mg).
  • the dosage of the statin compound may be about 0.1 to 50 mg, preferably 0.5 to 40 mg, more preferably about 1 to 30 mg (for example, 1 to 10 mg) per day for an adult.
  • the pharmaceutical composition of the present invention may be administered once per day, or may be administered a plurality of times (for example, about 2 to 5 times).
  • Examples 1-7 [Preparation of solid dispersion and tablets] Fenofibrate (5 g), sodium lauryl sulfate (SLS, 0.5 g) and hydroxypropylmethylcellulose 2910 (HPMC 2910, 0.5 g) were dissolved in an ethanol / acetone mixture (volume ratio 1: 1), and 50 mL solution (temperature Solution form at 10 ° C. and 0 ° C.).
  • SLS sodium lauryl sulfate
  • HPMC 2910 hydroxypropylmethylcellulose 2910
  • the characteristics of the spherical first porous carrier and the amorphous second porous carrier are as follows.
  • the obtained suspension was spray-dried at 80 ° C. in a nitrogen atmosphere using a spray dryer (“GS31” manufactured by Yamato Scientific Co., Ltd.) to obtain a solid dispersion powder.
  • the obtained solid dispersion powder and disintegrant (croscarmellose sodium) were weighed and mixed in a mortar, and then compressed at 50 kN to produce a slug tablet.
  • the slug tablet was crushed and passed through a sieve having an opening of 710 ⁇ m to obtain granules.
  • a lubricant magnesium stearate
  • HPLC high performance liquid chromatography
  • Table 3 shows the formulation (ratio of each component: parts by weight).
  • Control preparation Fenofibrate micronized preparation obtained by co-micronizing fenofibrate and surfactant and containing 67 mg of fenofibrate (Asuka Pharmaceutical Co., Ltd., Lipidil (registered trademark) capsule 67) is used as a control preparation It was.
  • [Absorptive] Dogs male beagle, 21-24 months old were fasted overnight and fed for 30 minutes, then about 15 minutes later, the tablet of Example 3 and the control preparation were each orally administered with 30 mL of water. Drinking water was free after administration. Before and after administration, after 0.5 to 25 hours (0.5 hours, 1 hour, 1.5 hours, 2, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours and 24 hours) About 1 mL of blood was collected from the left and right forearm scalp veins.
  • Example 3 showed the same absorbability as that of the control preparation although the content of the active ingredient was small.
  • Example 8 [Preparation of solid dispersion and tablets]
  • the first porous carrier is spherical and has the following characteristics: A solid dispersion powder was obtained in the same manner as in Example 1 except that HPC was used in place of HPMC2910, using hydrous silicon dioxide having a water content ("Syrosphere C-1504" manufactured by Fuji Silysia Chemical Co., Ltd.).
  • disintegrant croscarmellose sodium
  • lubricant magnesium stearate
  • Example 8 For the preparation of Example 8 and the control preparation, a dissolution test was conducted by the paddle method in the same manner as in Example 1, and the results shown in FIG. 6 were obtained. As is apparent from FIG. 6, the tablet of Example 8 showed high dissolution properties with respect to the control preparation despite the low content of the active ingredient.
  • Example 9 [Preparation of solid dispersion and tablets] Instead of the spherical first porous carrier used in Example 1, spherical silicon-containing silicon dioxide (“Syrosphere C-1504” manufactured by Fuji Silysia Chemical Co., Ltd.) was used as the first porous carrier. A solid dispersion powder was obtained in the same manner as in Example 1 except that the ratio of fenofibrate to the first porous carrier was adjusted and HPC was used instead of HPMC2910.
  • disintegrant croscarmellose sodium
  • lubricant magnesium stearate
  • Example 10 [Preparation of solid dispersion and tablets] Instead of the spherical first porous carrier used in Example 1, spherical silicon-containing silicon dioxide (“Syrosphere C-1504” manufactured by Fuji Silysia Chemical Co., Ltd.) was used as the first porous carrier. A solid dispersion powder was obtained in the same manner as in Example 1 except that the ratio of fenofibrate to the first porous carrier was adjusted and HPC was used instead of HPMC2910.
  • disintegrant croscarmellose sodium
  • lubricant magnesium stearate
  • Example 11 The solid dispersion powder obtained in Example 8, powdered pitavastatin (pitavastatin calcium), and disintegrant (croscarmellose sodium) were weighed and mixed in a mortar, and then compressed at 50 kN to produce a slug tablet. did. The slug tablet was crushed and passed through a sieve having an opening of 710 ⁇ m to obtain granules. A lubricant (magnesium stearate) was added to and mixed with the obtained granules, and compression-molded at 50 kN to obtain tablets.
  • powdered pitavastatin pitavastatin calcium
  • disintegrant croscarmellose sodium
  • the formulation per tablet (175.2 mg) was: fenofibrate 53.3 mg, pitavastatin 2 mg, first porous carrier 53.3 mg, SLS 1.9 mg, HPC 10.7 mg, disintegrant 53.5 mg, lubricant It is 2.7 mg of the agent.
  • Comparative Example 1 100 parts by weight of fenofibrate (average particle size 5 ⁇ m) obtained by co-pulverizing fenofibrate in the presence of a surfactant (SLS), an excipient (lactose hydrate), and a binder (pregelatinized starch)
  • SLS surfactant
  • lactose hydrate lactose hydrate
  • binder pregelatinized starch
  • a fenofibrate micronized preparation containing 3 parts by weight of powdered pitavastatin (pitavastatin calcium) was mixed, and tablets were obtained in the same manner as in Example 1 using a disintegrant (crospovidone) and a lubricant (magnesium stearate). It was.
  • the tablet formulation is as follows.
  • Example 11 and Comparative Example 1 elution of pitavastatin showed the same behavior, with an elution rate of 90% or more in 10 minutes and an elution rate of 95% or more in 15 minutes.
  • the elution test of fenofibrate was performed at a rotational speed of 100 revolutions per minute using a sodium lauryl sulfate solution as an eluent.
  • a tablet was obtained in the same manner as in Example 1 using a lubricant (magnesium stearate).
  • HPLC high performance liquid chromatography
  • the content of fenofibrate was about 53.3 mg and the content of rosuvastatin was 2.5 mg per tablet.
  • the active ingredient content in the tablet was about 53.3 mg fenofibrate content and 5 mg atorvastatin content per tablet.
  • a tablet was obtained in the same manner as in Example 1 using a powder (magnesium stearate). The content of the active ingredient in the tablet was about 53.3 mg of fenofibrate content and 10 mg of ezetimibe content per tablet.
  • a tablet was obtained in the same manner as in Example 1 using a powder (magnesium stearate).
  • the active ingredient content in the tablet was about 53.3 mg fenofibrate content and 2 mg candesartan cilexetil content per tablet.
  • a tablet was obtained in the same manner as in Example 1 using a powder (magnesium stearate). The active ingredient content in the tablet was about 53.3 mg fenofibrate content and 25 mg losartan content per tablet.
  • a tablet was obtained in the same manner as in Example 1 using a lubricant (magnesium stearate). The content of the active ingredient in the tablet was about 53.3 mg of fenofibrate content and 15 mg of pioglitazone per tablet.
  • Example 25 [Preparation of solid dispersion and tablets]
  • the first porous carrier is spherical and has the following characteristics: A solid dispersion powder was obtained in the same manner as in Example 1 except that HPC was used in addition to HPMC2910 using hydrous silicon dioxide having a water content ("Aeropearl 300/30" manufactured by Degussa).
  • disintegrants croscarmellose sodium and crospovidone
  • a lubricant magnesium stearate
  • tablets were obtained in the same manner as in Example 1.
  • the formulation per tablet (175.4 mg) is 53.3 mg of fenofibrate, 53.3 mg of the first porous carrier, SLS 1.9 mg, HPMC2910 5.35 mg, HPC 5.35 mg, disintegrant 53.5 mg ( Croscarmellose sodium 26.75 mg, crospovidone 26.75 mg) and lubricant 2.7 mg.
  • Example 25 For the preparation of Example 25 and the control preparation, a dissolution test was performed by the paddle method in the same manner as in Example 1, and the results shown in FIG. 9 were obtained. As is apparent from FIG. 9, the tablet of Example 25 showed high dissolution properties with respect to the control preparation despite the low content of the active ingredient.
  • Formulation Example 1 (tablet) Spray drying was performed in the same manner as in Example 1 to obtain a solid dispersion. This solid dispersion and the following carrier components were mixed, and then compressed and tableted at 5 kN to obtain tablets. In addition, the following ratio is the ratio (weight%) of the component in a tablet.
  • Example 2 41% by weight of solid dispersion of Example 1 Lactose 39% by weight 9% by weight of crystalline cellulose Crospovidone 9% by weight Talc 1% by weight Sucrose fatty acid ester 1% by weight Formulation Example 2 (tablet) Spray drying was performed in the same manner as in Example 5 to obtain a solid dispersion. This solid dispersion and the following carrier components were mixed, and then compressed and tableted at 5 kN to obtain tablets. In addition, the following ratio is the ratio (weight%) of the component in a tablet.
  • Example 5 54% by weight of solid dispersion of Example 5 D-mannitol 22% by weight Crospovidone 22% by weight Magnesium stearate 2% by weight Formulation Example 3 (Capsule) Spray drying was performed in the same manner as in Example 7 to obtain a solid dispersion powder.
  • the obtained solid dispersion powder, D-mannitol and croscarmellose sodium were mixed, and the mixture was compressed at 20 kN to produce slug tablets.
  • the slug tablet was crushed and granules were obtained through a sieve having an opening of 710 ⁇ m.
  • the obtained granules were filled with about 197 mg of gelatin capsules to prepare capsules.
  • the following ratio is a ratio of the component with respect to 100 weight% of capsule contents.
  • the solid dispersion and the pharmaceutical composition of the present invention the elution or dispersibility of the active ingredient and the bioavailability are remarkably improved, and the content of the active ingredient in the pharmaceutical preparation can be reduced.
  • the shape can be miniaturized. Therefore, the pharmaceutical composition is excellent in ingestibility and effective in improving patient compliance.
  • the solid dispersion and pharmaceutical composition of the present invention can be used as a preventive and / or therapeutic agent for various diseases such as metabolic syndrome, hyperlipidemia, diabetes, diabetic complications, etc., depending on the type of active ingredient. .

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Abstract

L'invention concerne un procédé de production d'une dispersion solide qui comprend l'imprégnation, sans traitement à l'aide d'un fluide supercritique, d'un véhicule poreux en poudre contenant un véhicule siliceux poreux (par exemple, un véhicule siliceux sphérique comme de la silice poreuse sphérique) qui présente une perte de poids inférieure ou égale à 4 % en poids lorsqu'il est chauffé à 950°C pendant 2 heures avec une solution de solvant organique composée d'un ingrédient actif légèrement hydrosoluble, puis le retrait du solvant organique du système obtenu pour former une dispersion solide comprenant le véhicule poreux et l'ingrédient actif supporté par celui-ci. Le véhicule siliceux poreux peut être de la silice sphérique présentant un diamètre de pore moyen de 10 à 40 nm et une absorption d'huile de 175 à 500 ml/100 g. Les compositions pharmaceutiques (comprimés, granules ou capsules par exemple) peuvent être préparées au moyen de la dispersion solide et des véhicules de qualité pharmaceutique. La dispersion solide et les compositions pharmaceutiques (ou préparations pharmaceutiques) permettent l'amélioration de la dissolution et de la biodisponibilité d'ingrédients actifs légèrement hydrosolubles (comme des composés fibrates).
PCT/JP2009/054517 2008-03-11 2009-03-10 Dispersion solide, compositions pharmaceutiques comprenant celle-ci, et procédés de production associés WO2009113522A1 (fr)

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ES09718988T ES2635767T3 (es) 2008-03-11 2009-03-10 Dispersión sólida, composiciones farmacéuticas que contienen la misma, y procedimientos de producción de ambas
JP2010502820A JP5437232B2 (ja) 2008-03-11 2009-03-10 固体分散体とその医薬組成物、並びにそれらの製造方法
EP09718988.0A EP2251038B1 (fr) 2008-03-11 2009-03-10 Dispersion solide, compositions pharmaceutiques comprenant celle-ci, et procédés de production associés
CA2718255A CA2718255C (fr) 2008-03-11 2009-03-10 Dispersion solide, compositions pharmaceutiques comprenant celle-ci, et procedes de production associes
CN2009801129958A CN102083467B (zh) 2008-03-11 2009-03-10 固体分散体及其药物组合物、以及它们的制备方法
US12/922,029 US8722094B2 (en) 2008-03-11 2009-03-10 Solid dispersion and pharmaceutical composition of the same, and production processes thereof
AU2009224418A AU2009224418B2 (en) 2008-03-11 2009-03-10 Solid dispersion, pharmaceutical compositions containing the same, and processes for the production of both

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EP2251038A1 (fr) 2010-11-17
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US8722094B2 (en) 2014-05-13
KR20100128322A (ko) 2010-12-07
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CA2718255A1 (fr) 2009-09-17
CN102083467B (zh) 2013-12-25
AU2009224418B2 (en) 2014-12-11
EP2251038B1 (fr) 2017-05-10
AU2009224418A2 (en) 2010-10-28
CN102083467A (zh) 2011-06-01
AU2009224418A1 (en) 2009-09-17
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